Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year, and it can take several years before the correct clinical diagnosis is obvious.
The diagnosis of AS rests on a combination of clinical features and molecular genetic testing and/or cytogenetic analysis. Consensus clinical diagnostic criteria for AS have been developed. Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 78% of individuals with AS, including those with a deletion, uniparental disomy (UPD), or an imprinting defect (ID); fewer than 1% of individuals have a cytogenetically visible chromosome rearrangement (i.e., translocation or inversion). UBE3A sequence analysis detects mutations in an additional approximately 11% of individuals. Accordingly, molecular genetic testing (methylation analysis and UBE3A sequence analysis) identifies alterations in approximately 90% of individuals. The remaining 10% of individuals with classic phenotypic features of AS have the disorder as a result of an as-yet unidentified genetic mechanism and thus are not amenable to diagnostic testing.
AS is caused by disruption of maternally imprinted UBE3A located within the 15q11.2-q13 Angelman syndrome/Prader-Willi syndrome (AS/PWS) region. The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function: typically less than 1% risk for probands with a deletion or UPD, and as high as 50% for probands with an ID or a mutation of UBE3A. Members of the mother's extended family are also at increased risk when an ID or a UBE3A mutation is present. Cytogenetically visible chromosome rearrangements may be inherited but are usually de novo. Prenatal testing for pregnancies at increased risk is possible when the underlying genetic mechanism is a deletion, UPD, an ID, a UBE3A mutation, or a chromosome rearrangement.